NZ190834A - Trans-dl-5-(alkyl or allyl)-4,4a,5,6,7,8,8a,9-octahydro-21 + pyrrolo(3,4-g)quinolines, - Google Patents
Trans-dl-5-(alkyl or allyl)-4,4a,5,6,7,8,8a,9-octahydro-21 + pyrrolo(3,4-g)quinolines,Info
- Publication number
- NZ190834A NZ190834A NZ190834A NZ19083479A NZ190834A NZ 190834 A NZ190834 A NZ 190834A NZ 190834 A NZ190834 A NZ 190834A NZ 19083479 A NZ19083479 A NZ 19083479A NZ 190834 A NZ190834 A NZ 190834A
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- Prior art keywords
- compound
- trans
- alkyl
- formula
- quinoline
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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Description
New Zealand Paient Spedficaiion for Paient Number 1 90834
190834
Priority Dat%{&): :7f.j.. ;(
Complete Specification Filed: ^.k'. k .1$ Glass: WP.MX
•/
PubHcstfcn Date: P.O. Journal, No:
iD'emm'
110
NEW ZEALAND PATENTS ACT, 1953
No.: Date:
A. J. P. & S. 7-1 -9"v tiMC
COMPLETE SPECIFICATION
OCTAHYDRO-2H-PYRROLO (3,4-0) QUINOLINES
xk/ We, ELI LILLY AND COMPANY, a corporation of the State of Indiana, United States of America, having a principal place of business at 307 East McCarty Street, City of Indianapolis, State of Indiana, United States of America hereby declare the invention for whichxk / we pray that a patent may be granted toXHSc/us, and the method by which it is to be performed, to be particularly described in and by the following statement:-
- 1 " (followed by page la)
190834
— I q ~
This invention provides trans-dl-5 and 7-substituted-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinolines of the following structure
R1-Nl 2
3
V
wherein
' /8\ F
i r7i ■A*?V
lz
R1 is H or alkyl;
is C^-C^ alkyl or allyl;
R3 is H or CI^X wherein X is CN, C0NH9, SC^CH^, SCH3 or OCH^; and the 4a, 8a bond is trans and, when R3 is CH2X, the compound is a 4a/3, 7/3, 8a^or 4a<?c, 8ap isomer or the racemate of these isomers; and the pharmaceutically-acceptable acid addition salts thereof.
The compounds of formula I can be prepared by reacting a compound of the formula
R3
i J,.r2
;vi
1 1
/ t ni j. ii _,
R —N • Id
m
190834
wherein
R1 is (C.-C-Jalkyl-CO;
2
R is H, C^-C^ alkyl, or allyl;
R3 is H or CH2Y; and
Y is CI, Br, OS02phenyl, O-tosyl, or OS02(C^-C^)alkyl; and the 4a, 8a bond is trans and, when
O .
R is CH2Y, the compound is a 4af3, 7|3, 8a< or 4a<x, lex, 8a|3
isomer or' the racemate of these isomers,
with base to provide a . compound of formula Id 'wherein R"*" is H;
optionally followed by reacting with an
alkyl halide to obtain a compound of formula 3d where R^" is C..-C., alkyl;
2
where R is H followed by reacting with an alkyl or allyl halide or reductive alkylation with an appropriate aldehyde and metal hydride to obtain 15 compound of formula Id where R^- is H or C] -c3 alkyl and R" is C1-C3 alkyl or allyl;
followed by reacting a compound of formula Id where R is CH2Y with sodium methvlate, methylmercaptan sodium salt, sodium cyanide, or sodium 20 methanesulfinate, to obtain a compound, of formula I where R3 is CH2X where X is CN, SCH^, SC^CH.,, or OCH ^; and optionally followed by reacting a cora-
3
pound of formula I where R is CH CN with hydration
3
2 5 to obtain a compound of formula I where R is ch2conh2.
In the above formula, the ring junction (the 4a, 8a bond) is trans and the compounds are obtained as a racemic pair. The two stereoisomers 30 constituting the racemate can be drawn as structures la and lb below
1 908 34
X DQGOA -3-
R -NL 2
|_|
1 p ,f
H A
2
la
In addition, introduction of a substituent at C-7 (R is other than H) creats a new chiral center and the compounds of that structure exist as 4 stereoisomers in two racemic pairs. The synthetic procedures to be set forth herein yield a single predominant racemate consisting of the 4a3,73,8aa isomer and its mirror image, the 4aa,7a,8a0 isomer. Resolution of this racemate into its component diastereoisomers can be readily accomplished by methods currently available in the art. Regardless of the structure currently assigned to a given isomer or racemate, this invention provides compounds of the above formula having dopaminergic activity, whether in pure form as a single di-astereoisomer or admixed with one, or more, less active or even inactive diastereoisomers.
Also within the scope of this invention are novel intermediates of the formula
190831
R3
A /i-R2
1 .)-
I J
wherein
R1 R2
R1-I 3
is H or (C^-C^)alkyl-CO(
is H, benzyl or C]_~C3 alkyl; and R3 is H, COO (C1-C3) alkyl, COOH, or CH^'1 wherein X"^" is OH, CI, 0S02 (C^-Calkyl, 0SO2 tolyl, or OSO phenyl;
13
with the proviso that both R and R° can
2
not be H when R is C^-C^ alkvl; and their acid addition salts.
In the above formulas, the term "C^-C^ alkyl "represents methyl, ethyl, n-propyl and iso-propyl.
The pharmaceutically-acceptable acid addition salts of this invention include salts derived from inorganic acids such as: hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid, phosphoric acid and the like, as well as salts derived from nontoxic organic acids such as aliphatic mono and dicarboxylic acids, phenyl-sub-stituted alkanoic acids, hydroxy alkanoic and
-s-
alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, 5 monohydrogenphosphate, dihydrogenphosphate, meta-
phosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, aerylate, formate, isobutyratecaprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, 10 sebacate, fumarate, maleate, mandelate,abutyne-1,4-dioate ,a hexyne-1,6-dioate, benzoate,acnloro-benzoate ,a methyIbenzoate ,a dinitrobenzoate,ahydroxy-benzoate,amethoxvbenzoate, phthalate, terephthalate, benzenesulfonate,atoluenesulfonate,a chlorobenzene-15 sulfonate,a xylenesulfonate, phenylacetate,aphenyl-propionate, aphenylbutyrate, citrate, lactate, j3-hydroxybutyrate, glycollate, malate, tartrate., methanesulfonate,apropanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and the like 20 salts.
The intermediates coming within the scope of Formula I form useful salts with all varieties of acids, not just non-toxic acids, and these salts are used for reaction and purification purposes. 25 Illustrative compounds falling within the scope of formula I include:
trans-dl-2,5-dimethyl-7-methylmercapto-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo(3,4-gjquinoline sulfate
U 90834
trans-dl- 2 , 5-dimethy 1- 7-methoxymethy 1-4,4a, 5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline sulfate trans-dl-5-methyl-4,4a,5,6,7,8, 8a,9-octa-hydro-2H-pyrrolo[3,4-g]quinoline hydrochloride trans-dl-5-isopropyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline trans-dl-2-methy1-5-n-propy1-7-methy1-sulfonylmethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline maleate trans-dl-5-ethy1-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline trans-dl-5-allyl-4,4a,5,6,7,8,8a,9-octa-hydro-2H-pyrrolo[3,4-g]quinoline.
3 .
The compounds of formula I in which R is
H are prepared according to the procedure outlined in Reaction Scheme I below. In Reaction Scheme I,
only one stereoisomer has been drawn for convenience,
but it should be remembered that each decahydro-
quinoline and each octahydropyrrolo[3,4-g]quinoline
2
exists as a racemate. In addition, R is other than H.
0 908 3 4-
Reaction Scheme I
I I
pyrrolidine acrylamide
\
\
/
acid catalyst
/
I
0-C0-Z
Z-C0-0-
II
/ \ / \ I k X
/\/\ LIAIH
h !i i
/
\
III H
R2X NaH
\ /
/\/\ 7 :T I
0
V R2
HCI
NaCNBHs
IV
/
H0-
I T I
\/#\/ HaS°4 /
Cr03
\
I I T
• H
VII I
VI R*
\
(CH3)2NCH(0Z")S
/
(CH3CO)SO
/
\
K gIyc i nate
0,
a * A
/
\
I T I
(CHs)aNo/
VIII
1908 3 4
*
2
CHaCO'
H
IX
X
In the above reaction scheme, Z-CO is an acyl protecting group in which Z is (C^-C^)alkyl, (C2-C3)-alkenyl, alkynyl, (C^-C^)cycloalkyl, phenyl or substituted phenyl wherein the substituting group can be methyl, methoxy, chloro and the like, at any position of the phenyl ring. Illustratively, Z-CO can be acetyl, propionyl, butyryl, propiolyl, acrylyl, benzoyl, p-toluyl, o-chlorobenzoyl, or m-methoxybenzoyl.
producing compound VIII in Reaction Scheme I (and compound XV in Reaction Scheme II below) have the general formula (CH^)2N-CH-(OZ1')2 in which Z'1 is (C^-Cg)alkyl, (C^-Cg)cycloalkyl, (C3~C4)alkenyl, (C^-C^)alkynyl and the like. We prefer to employ one of the commercially available acetals of dimethyl formamide; i.e.; the dimethyl, diethyl, diisopropyl, dibutyl, dicyclohexyl, dipropyl or dineopentyl acetals.
Acetals of dimethylformamide useful in
In accordance with Reaction Scheme 1/ a 4-acyloxycyclohexanone (II) prepared by the procedure of E.R.H. Jones and F. Sondheimer, J. Chem. Soc., 615, (19 49) is reacted with pyrrolidine in the presence of an acid catalyst to yield a pyrrolidine enamine. This enamine is in turn reacted with acrylamide to produce a mixture of dl-6-acyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and dl-6-acyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone represented by formula III, the dotted lines indicating the alternative positions of the double bond.
Next, the acidic nitrogen (apid,ic since it is alpha to a carbonyl group) is reacted v;ith a
2 .9
halide R X wherein is C]_-C3 alkyl, allyl or benzyl and X is a halogen such as CI, Br or I, in tne presence of sodium hydride to yield a mixture of dl-1-(C-^-C^) alkyl (or allyl or benzyl)-6-acyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and
Q
its A isomer (IV). Reduction of this amide with lithium aluminum hydride or other suitable organo-metallic reducing agent yields a mixture of dl-
1-(C,-C.J. alkyl (or allyl or benzyl)-6-hydroxy-
8
1,2,3,4,5,6,7,8-octahydroquinoline and its A isomer. In this reaction mixture, conditions are encountered which serve to hydrogenolyze the acyloxy group to a hydroxyl group at C-6. The dl-1- (^-C^) -alkyl (or allyl or benzyl)-6-hydroxyoctahydroquino-line mixture is next converted to an ammonium salt by treatment with hydrochloric acid, and the ammonium
'1908 3
-x 50C0A -10-
salt is then reduced with sodium cyanoborohydride to yield trans-dl-1-(C^-C3)alkyl (or allyl or benzyl)-6-hydroxydecahydroquinoline (VI). Next, the trans-dl-1- (C^-C^ alkyl, allyl, or benzyl)-6-hydroxy-5 decahydroquinoline (VI) is oxidized using, preferably, chromium trioxide in acetic acid, to yield the corresponding 6-oxo compound (VII). By adapting the procedure of Zav'yalof et al. C.A., 80, 59815z(1974), Izv. Akad. Nauk. SSSR. Ser. Khim 2572-7 (1973), this 10 6-oxo compound (VII) is reacted with dimethylform-amide dimethylacetal to yield a 7-dimethylamino-methylene-6-oxo-derivative (VIII). Reaction of this derivative with potassium glycinate followed by treatment of the thus formed intermediate product 15 with acetic anhydride yields a tricyclic derivative, trans-dl-2-acetyl-5-[(C^-C^)alkyl, allyl or benzyl)]-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline (IX). Removal of the acetyl group at N-2 with
2
base yields the dopamine agonist (X) when R is
(C,-C-J alkyl or allyl, or a useful intermediate when 2
R is benzyl.
Those compounds in which R^" is C^-C^ alkyl are prepared from compound X by taking advantage of the acidic hydrogen in the pyrrole ring and reacting 25 an anionic salt thereof, prepared from sodium hydride or other suitable base, with an alkyl halide, R^" X where R^" is (C^-C^) alkyl or allyl and X is CI, Br or I.
2
Those compounds in which R is benzyl can
2
be transformed into compounds in which R is
(C^-C^)alkyl or allyl as follows: the benzyl group
'90834
X GOCOA -11-
can be removed by reductive cleavage or by treatment with cyanogen bromide to yield, eventually, a com-
2
pound in which R is H. The usual conditions for removing an N-benzyl group are hydrogen with a 5 palladium-on-carbon catalyst or reaction with cyanogen bromide followed by reductive (Zn and acetic acid) cleavage of the N-cyano compound. This debenzylated compound can then be alkylated with an allyl or a lower alkyl halide, or alternatively it 10 may be reductively alkylated using acetaldehyde, propionaldehyde or other aldehyde with a metal hydride, such as sodium cyanoborohydride.
Compounds according to formula I above in
3
which R is other than H are prepared according to a 15 slightly different, but comparable, synthetic route illustrated in Reaction Scheme II below. As in Reaction Scheme I, the synthetic procedure is illustrated for convenience with respect to a single stereoisomer (referring to the bridgehead config-20 uration) the 4a0,8aa isomer.
1 90834
~X,_ 50 6 OA
Reaction Scheme II
0
\
/*\ R2NHS
* * CHs=C-COOZ' / • I
I CHsHal
O-CO-Z
II
H
M-*' »>Z' ✓ Z'OH / OH"
\ A /\
I :I f
VY
-C00Z'
XI R'
\
ac i d BH4~
/
/
\ HCI \
; ^
XIII
\
vi^
f-COOZ'
►V
pyrid i ne*HCI Cr03
H , XII
R2
/
H
0=^ Y X|-C00Z'
MV
(CH3)eNCH(0Z'')a \
/
H
XIV
(CHsJaNCH XV
Q~/ Y Xf-C00Z'
= W*
\
R
K g!yc i nate acetic anhydride
/
H
• — ©
yCH=f/ Xf/ \-C00Z'
/ hydro I ys i s Ac!
\
/ HN^
H
CH=f/ \-C00Z'
t i r
CH=*viv*
H
XVI
I
RZ XVII
*
190834
-13—
wherein Z and Z *' have the same significance as in Reaction Scheme I, Hal is chloro or bromo and Z' is part of a readily hydrolyzable group Z'O-CO including (C^-C2) alkyl, phenyl substituted (C-^-C^) alkyl, illus-5 tratively benzyl, phenethyl, p-methoxybenzyl, methyl, ethyl and others.
In accordance with the Reaction Scheme II, a 4-acyloxycyclohexanone (II) is reacted with an a-halomethylacrylate ester, for illustrative pur-10 poses, the ethyl ester, and an amine, R%IH2, wherein R2 is C^-C^ alkyl, allyl or benzyl. The product of this reaction is a mixture of dl-l-substituted-3-ethoxycarbony 1-6- acyloxy- 1 , 2,3,4,5,6,7,8-octahydroquinoline and dl-1-substituted-3-ethoxycarbony1-6-acyloxy-15 1,2,3,4,4a,5,6,7-octahydroquinoline represented by XI in which the dotted line indicates the alternate positions of the double bond. The hydrochloride salts of these isomers are prepared and the resulting mixture reduced with sodium cyanoborohydride to yield 20 trans-dl-1-substituted-3-ethoxycarbony1-6-acyloxy-
decahydroquinoline (XII). Hydrolysis of this diester to yield a 6-hydroxy-3-carboxylic acid followed by reesterification of the carboxylic acid group with ethanol or other alcohol in the presence of acid 25 yields trans-dl-l-substituted-3-ethoxycarbony1-6-
hydroxydecahydroquinoline (XIII). Oxidation of the hydroxy group with Sarett's Reagent (pyridine hydrochloride and chromium trioxide) produces the corresponding 6-oxo compound (XIV). Treatment of this 30 6-oxo derivative with dimethylformamide dimethyl-
X" GOGOA.
r1 908
acetal results in reaction at C-7 (adjacent to the keto group) to give trans-dl-l-substituted-3-ethoxycarbony 1- 6-oxo- 7- (dimethylaminomethylene)decahydro-quinoline (XV). Reaction of this derivative with 5 potassium glycinate followed by a treatment of the intermediate product with acetic anhydride gives the tricyclic derivative, trans-dl-2-acetyl-5-substi-tuted-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline (XVI). Hydrolysis with 10 sodium ethoxide in ethanol yields the NH compound (XVII).
The octahydropyrrolo[3,4-g]quinoline of Formula XVI represents a single isomer. The mirror image of XVI is produced concomitantly and is in-15 eluded within the scope of this invention. We believe, based upon analogy with the D-ergolines, • that the diastereoisomer XVI as drawn is the isomer having dopamine agonist activity. The trans-dl racemate, which contains XVI and its mirror image, is 20 of course useful as a dopamine agonist, even though most of the desired activity resides in one of its component stereoisomers.
Compounds according to XVI above in which
2
R is methyl or benzyl can be transformed into
2
compounds in which R is ethyl, allyl or n-propyl by reaction with cyanogen bromide. The intermediate 5-cyano derivative can be reductively cleaved (zinc
2
plus acetic acid) to yield a compound in which R is H. In addition, the benzyl group can be removed by 30 hydrogenation with palladium-on-carbon to yield those
190834
-*-53-&£A
2
intermediates in which R =H. Alkylation of those
2
compounds in which R is H can be accomplished by
2 2 2
reaction with an alkyl halide, R CI, R Br or R I.
Alternatively, the secondary amine can be reacted
with acetadehyde, acrolein, or propionaldehyde under reducing conditions (NaBH^CN) to yield an N-ethyl,
N-allyl or N-n-propyl derivative.
The dopamine agonists of formula I in
3
which R is other than H; i.e. those compounds in 10 which R3 is CI^X wherein X is CN, OCH^, SCH^,
SC^CH^ or CO-NH2, are prepared according to Reaction Scheme III below
1 908
A
Reaction Scheme III
HN^
H
CH=f/ Xfy \— C00Z'
CH=J CH=l
LiAIH
\
XVII
/
Hl<^
H
.CH-^ Xf/ \-CHsOH
A T I
1 '4V1
XVIII
tosyI-CI (Ci-Ca)alkyl-SOsCI phenyI-SO2CI
\
SOCI2 PC 15 POCIa PBr3
/
H _
/V/\
.CH=f y V— CHsY
<i1 r
\
1 R
NaCN CHaSNa CHsONa CH3SOaNa /
XIX
,CH=f/ Xt7 Xf— CHzX
1 i r
XX
R
II 908
-X»-50G0A -17-
wherein Z' and R have the same significance as before, Y is a "leaving" group: CI, Br, OSO-phenyl,
2
0-tosyl or S02 (C^-C^)alkyl, R is H, SC^phenyl, tosyl or S02 (C^-C^)alkyl, and X is CN, SCH^, OCH-j or 5 SC^CH^. The acetyl group of a compound according to XVI in Reaction Scheme II is hydrolyzed with sodium ethoxide in ethanol or sodium methoxide in methanol to yield a desacetyl derivative. The carboalkoxy group is then reduced with a metal hydride such as 10 LiAlH^ to an hydroxymethyl group, thus providing a trans-dl-5-substituted-7-hydroxymethyl-4,4a,5,6,-7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline (XVIII). The hydroxyl can be replaced with a chlorine or bromine leaving group and the resulting chloro-15 methyl or bromomethyl compound reacted with NaCN to yield a compound in which R3 is CH2~CN. Other leaving, groups—groups readily replaced by a nucleophilic reagent--such as the mesyloxy, p-tosyloxy, benzenesulfonyloxy and the like groups 20 [when X in formula I, la or lb or Y in formula
XIX, is OSO^(C^-C^)alkyl, OSO^phenyl or 0S02tolyl] can be produced by acylation of the hydroxy group with a sulfonyl halide. Reaction of the thus-produced compound with sodium methylate, methy1-25 mercaptan sodium salt, sodium cyanide, sodium methanesulfinate or other basic salts of methanol,
methylmercaptan yields compounds according to
3
formula I, la or lb in which R is CI^X and X is SCH^, OCH^, CN or SO^H^. Compounds in which X is 30 C0NH2 are prepared by hydration of the corresponding cyano compound.
190834
X-jQGOA -18-
Compounds represented by formulas I, la and
2
lb, in which R is H and by formulas IX, and X above have two centers of assymetry, the ring junction carbons at 8a and 4a. Thus, the compounds can occur
as two racemates, ordinarily denominated as the trans-dl racemate and the cis-dl racemate. It is believed, however, according to the best evidence from NMR spectral data of the maleate salt of the
2
compound according to Formula X above wherein R is 10 benzyl, that the cyanoborohydride reduction (going from V to VI in Reaction Scheme I) yields a transfused decahydroquinoline. While the arguments for the trans configuration based upon NMR spectral data are compelling, an X-ray crystallographic
investigation has also been carried out on the nicely
2
crystalline enaminoketone (VIII) in which R is methyl, the precursor of the pyrrole (X). This X-ray analysis indicated clearly that the ring junction is trans. Thus, only the trans racemate is 20 prepared by the synthetic procedures disclosed herein and the compounds of formula I are preferably represented as the trans-dl steroisomers la and lb
3
above in which R is H. Resolution of this racemate into its optical antipodes can be accomplished by 25 procedures known to those skilled in the art, and the individual trans-d and trans-1 isomers are included within the scope of this invention.
When R is other than H, a third chiral center is introduced at C-7, thereby doubling, at 30 least in theory, the number of isomers produced by
&
1 908
X 50G0A -19-
Reaction Schemes II and III. However, it is presently believed that the configuration of the C-7 group is "trans" to that of the 8a hydrogen. Thus
3
in la above, R when it is other than H, has a beta 5 configuration with the 8a hydrogen having an alpha configuration. In the mirror image lb, the 8a hydrogen is beta and the C-7 substituent alpha.
Thus the dl-trans-7-substituted octahydropyrrolo-[3,4-g]quinolines of formula I are provided sub-10 stantially as a single racemate.
In addition, it is apparent from an inspection of the dl-trans-1 (substituted)-6-keto decahydroquinoline (VII) that reaction with dime thy If ormamide dimethylacetal could take place at 15 either C-5 or C-7 since both these carbons are ortho to the ketone group and are thus "activated". The same X-ray crystallographic analysis of the enamine (VIII) clearly indicated that reaction had taken place at C-7 rather than C-5. Hence, the final 20 tricyclic compounds IX, X, XVI and I are the linear pyrrolo[3,4-g]quinolines rather than the angular tricyclic compounds (which would be named as 4,4a,-5,6,7,8,8a,9-octahydro-lH-pyrrolo[2,3— i]quinolines).
This invention is further illustrated by 25 the following specific examples.
190834
X- 50 0OA -20-
STARTING MATERIALS Example A
Preparation of trans-dl-2-Acetyl-5-methyl-4,4a,5, 6,7,8,8a,9-octahydro-2H-pyrrold B,4-g]quino-line.
A reaction mixture was prepared from 52 g. of 4-benzoyloxycyclohexanone, 30 ml. of pyrrolidine, a few crystals of p-toluene sulfonic acid mono-hydrate, and 1000 ml. of benzene. The reaction mixture was heated to refluxing temperature under a nitrogen atmosphere for one hour in an apparatus equipped with a Dean-Stark water trap. The reaction mixture was then cooled and the solvent and other volatile materials removed by evaporation in vacuo. The residue, comprising the pyrrolidine enamine of 4-benzoyloxycyclohexanone formed in the above reaction was dissolved without further purification in 1000 ml. of dioxane. 42.6 g. of acrylamide were added. This new reaction mixture was heated under a nitrogen atmosphere at reflux temperature for twenty-one hours. Thin-layer chromatography of the reaction mixture indicated one major spot. The reaction mixture was cooled and the volatile constituents removed by evaporation in vacuo. A chloroform solution of the residue comprising 6-benzoyloxy-3,4,5,6,7,8-hexahydro-lH-quinolin-2-one and the isomeric product 6-benzoyloxy-3,4,4a,5,-6,7-hexahydro-lH-quinolin-2-one was chromatographed 3Q over 350 g. of florisil using chloroform containing
190834
X-5060A
increasing quantities of ethanol (0 to 2 percent) as the eluant. Fractions found to contain 6-benzoyl-oxy-3,4,5,6, 7,8-hexahydro-lH-quinolin-2-one and its isomer by thin-layer chromatography were combined 5 and the solvent removed therefrom in vacuo. The resulting residue was crystallized by triturating with hexane to yield a crystalline mixture of 6-benzoyl-oxy-3,4,5,6,7,8-hexahydro-lH-quinolin-2-one and the corresponding 3,4,4a,5,6,7-hexahydro derivative. 10 The mixture melted in the range 130-150°C. after recrystallization from an ether-hexane solvent mixture.
Analysis: Calculated: C, 70.83; H, 6.32;
N, 5.16;
Found: C, 71.05; H, 6.19;
N, 5.33.
NMR of the product isolated above indicated that the mixture contained about 60 percent 2Q of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-lH-quino-lin-2-one and 40% of the 3,4,4a,5,6,7-hexahydro isomer.
46.5 g. of the above isomer mixture were dissolved in 400 ml. of tetrahydrofuran (THF). 80 ml. of methyl iodide were added and the resulting
2 o mixture cooled in an ice-water bath. 9.6 g. of sodium hydride (as a 50 percent suspension in mineral oil) were added in portions. After all of the sodium hydride suspension had been added, the _n cooling bath was removed and the reaction mixture
190834
X-50 60A
stirred at ambient temperature under a nitrogen atmosphere for about 4 hours. The reaction mixture was then diluted with water and the aqueous mixture thoroughly extracted with chloroform. The chloro-5 form extracts were combined and the combined -extracts washed with saturated aqueous sodium chloride and dried. The chloroform was removed by evaporation to dryness in vacuo leaving as a residue an orange oil weighing 47.3 g. Recrystallization 10 from an ether-hexane solvent mixture yielded crystals of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer.
Analysis: Calculated: C, 71.56; H, 6.71; N, 4.91; 15 Found: C, 71.33; H, 6.90; N, 4.67.
Following the above procedure, 59 g. of a mixture of 6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and 6-benzoyloxy-3,4,4a,5,6,-2Q 7-hexahydro-2(1H)-quinolinone were reacted with n-propyl iodide in the presence of sodium hydride to yield l-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexa-hydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer. The compounds were 2!- purified by chromatography over florisil using an ether-chloroform solvent mixture as the eluant.
Also following the above procedure, a mixture of the l-benzyl-6-benzoyloxyhexahydro-2(1H)-quinolinones was prepared by substituting benzyl bromide for methyl iodide.
190834
A solution of 47.3 g. of a mixture of 1-methyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer as obtained above were dissolved in 5 800 ml. of THF and the solution cooled to about 0°C. 20 g. of lithium aluminum hydride were added thereto in portions and the resulting mixture refluxed for four hours under a nitrogen atmosphere. The reaction mixture was cooled and excess lithium aluminum 10 hydride destroyed by the addition of ethyl acetate. 10% sodium hydroxide was then added and the mixture diluted with water to decompose any organometallics present. The aqueous mixture was extracted several times with a chloroform-isopropanol solvent mixture. 15 The organic extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded as a residue a mixture of the enamines--l-methyl-6-hydroxy-l,2,3,4,5,6,7,8-octahydroquino-20 line and l-methyl-6-hydroxy-l,2,3,4,4a,5,6,7-
octahydroquinoline—formed in the above reaction. (The lithium aluminum hydride reduction served to remove the benzoyl group at C-6 as a benzyl alcohol moiety, leaving a free hydroxyl in that position of -25 the ring). The above residue, without further purification, was dissolved in about 300 ml. of ether and the ethereal solution saturated with gaseous hydrogen chloride, thus forming the hydrochloride salt of the enamine mixture. The ether was 30 removed by decantation and the residue dissolved in
190834
X"1 50 GO A -24-
a mixture of 200 ml. of THF and 50 ml. of methanol. This solution was cooled in an ice water bath. 12 g. of sodium cyanoborohydride were added with cooling and stirring. After all of the cyano-5 borohydride had been added, the reaction mixture was stirred for another 6 0 minutes and then poured over a mixture of ice and IN aqueous hydrochloric acid. The acidic aqueous solution was extracted with chloroform and the chloroform extract discarded. 10 The solution was then made basic with 14N aqueous ammonium hydroxide. Trans-dl-l-methyl-6-hydroxy-decahydroquinoline formed in the above reaction, being insoluble in the alkaline medium, separated and was extracted several times with a chloroform-15 isopropanol solvent mixture. The combined extracts were washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded 15 g. of trans-dl-l-methyl-6-hydroxydecahydroquino-' line.
Following the above sequence of reactions,
a mixture of l-n-propyl-6-benzoyloxy-3,4,5,6,7,8-
hexahydro-2(1H)-quinolinone and the corresponding
3,4,4a,5,6,7-hexahydro isomer were first reduced with lithium aluminum hydride to yield a mixture of 4 3 8
A and A l-n-propyl-6-hydroxyoctahydroquinolines which was converted by treatment with ethereal hydrogen chloride to the enamine hydrochloride. Reduction of this intermediate enamine hydrochloride with sodium cyanoborohydride yielded trans-dl-30 l-n-propyl-6-hydroxydecahydroquinoline (56 g. of
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X-50 60A -25-
starting material yielded 30 g. of product). Also following the above procedure, 1-benzy1-6-benzoyl-oxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone in admixture with l-benzyl-6-benzoyloxy-3,4,4a,5,-5 6,7-hexahydro-2(1H)-quinolinone was reduced with lithium aluminum hydride to yield the corresponding l-benzyl-6-hydroxy-l,2,3,4,5,6,7,8-octahydroquino-line and 1-benzy1-6-hydroxy-l,2,3,4,4a,5,6,7-octahydroquinoline as a mixture, treatment of which 10 with ethereal hydrogen hydrochloride yielded the enamine salt. Reduction of the enamine salt with sodium cyanoborohydride gave l-benzyl-6-hydroxydeca-hydroquinoline (65 g. of starting mixture yielded 49.6 g. of final product).
Fifteen grams of trans-dl-1-methy1-6-
hydroxydecahydroquinoline were dissolved in 250 ml. of 6N aqueous isulfuric acid. The solution was cooled in an ice-water bath. A solution of 9 g. of chromium trioxide in 60 ml. of 6N aqueous sulfuric 20 acid were added thereto with stirring in dropwise fashion over a 10-minute period. The cooling bath was removed and the reaction mixture stirred for an additional. 60 minutes at ambient temperature. The excess oxidizing agent was decomposed by adding 25 isopropanol to the reaction mixture. The reaction mixture was next poured over ice and the acidic aqueous solution made basic with 14N aqueous ammonium hydroxide, trans-dl-1-Methyl-6-oxodeca-hydroquinoline thus formed, being insoluble in the 30 alkaline layer, separated and was extracted several
190834
•fr ■ 50 GOA -26-
times with a mixture of chloroform and isopropanol. The extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo 5 yielded trans-dl-1-methy1-6-oxodecahydroquinoline boiling in the range 105-116°C. at 6 torr; yield = 7.7 g. (45%).
Following the above procedure, 29.5 g. of trans-dl-l-n-propyl-6-hydroxydecahydroquinoline were 10 dissolved in 300 ml. of glacial acetic acid to which was added 8 ml. of 18N aqueous sulfuric acid. 55 ml. of a solution of 26.7 g. of chromium trioxide in 2 3 ml. of 18M sulfuric acid were added in drop-wise fashion. trans-dl-l-n-Propyl-6-oxodecahydro-15 quinoline formed in the above reaction was isolated by the above procedure; yield = 21.4 g. Still following the above procedure, 49.6 g. of trans-dl- 1-benzy1-6-hydroxy-decahydroquinoline were oxidized with chromium trioxide in sulfuric acid to 20 yield trans-dl-l-benzy1-6-oxodecahydroquinoline; yield = 21.1 g. of a dark oil.
A reaction mixture was prepared from 7.7 g. of trans-dl-1-methy1-6-oxodecahydroquinoline, 36 g. of the dimethyl acetal of dimethylformamide 25 and 250 ml. of benzene. Benzene was removed by distillation at atmospheric pressure under nitrogen until about 1/2 the original volume remained (1.25 hours). Sufficient benzene was then added to make up the volume to the original volume and the process 30 was repeated (four times). All of the benzene was
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■S-5060A -27-
finally removed by evaporation in vacuo and the resulting residue dissolved in 100 g. of dimethyl-formamide dimethylacetal. This solution was heated to refluxing temperature under nitrogen for 20 5 hours. The reaction mixture was then evaporated in vacuo and a chloroform solution of the residue chromatographed over 150 g. of florisil using as the eluant, methylene dichloride containing increasing amounts (1-5%) of methanol. Fractions 10 containing similar compounds as shown by TLC were combined. The third substance to come off the column was a yellow solid (wt = 3 g.) The solid was heated with 100 ml. of ether and the resulting solution filtered. Concentration of the filtrate to 15 about 50 ml. yielded 590 mg. of trans-dl-1-methy1-6-oxo-7-dimethylaminomethylenedecahydroquinoline melting at 107-109°C.
Analysis: Calculated: C, 70.23; H, 9.97; N, 12.60;
Found: C, 70.17; H, 9.74; N, 12.87.
The above reaction was repeated except that trans-dl-l-n-propyl-6-oxodecahydroquinoline was used as a starting material and the product was chromatographed over florisil using chloroform 22 containing increasing quantities of methanol (1-5%) as the eluant. trans-dl-l-n-Propyl-6-oxo-7-dimethylaminomethylenedecahydroquinoline was obtained.
Following the above procedure, trans-dl-l-benzy 1-6-oxodecahydroquinoline was reacted with
Jv o dimethylformamide dimethylacetal to yield trans-
190834
~X™~50 GOA
-2 8-
dl-1-benzy1-6-oxo-7-dimethylaminomethylenedecahydro-quinoline melting at 109-111°C. after recrystal-lization from an ether-hexane solvent mixture.
Analysis: Calculated: C, 76.47; H, 8.78; N, 9.29;
Found: C, 76.25; H, 8.66; N, 9.36.
The potassium salt of glycine was prepared by reacting 975 mg. of glycine with 730 mg. of potassium hydroxide in 100 ml. of anhydrous ethanol. 2.8 g. of trans-dl-l-methyl-6-oxo-7-dimethylamino-methylenedecahydroquinoline were added and the resulting mixture heated at reflux temperature under nitrogen for about 3 hours. The reaction mixture was cooled, the volatile constituents removed in vacuo and the residue diluted with ether. The resulting mixture was filtered.and the adduct weighed 3.5 g. The glycine adduct was then cyclized, decarboxylated and acetylated by heating with 100 ml. of acetic anhydride at reflux temperature under nitrogen for about 45 minutes. The acetyla-tion mixture was cooled and the volatile constituents removed by evaporation to dryness. The residue, comprising trans-dl-2-acetyl-5-methy1-4,4a,5,6,-7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline was suspended in methylene dichloride and the suspension filtered to yield 1.7 g. of solid. The methylene dichloride filtrate was chromatographed over 150 g. of florisil using methylene dichloride containing increasing (0-5%) amounts of methanol as the eluant. Fractions shown by TLC to contain the same substance
190834
-3E-50G0A -29-
were combined, and the combined fractions washed with sodium bicarbonate and saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo yielded a residue which was rechromatographed 5 over 30 g. of florisil using chloroform containing 5% methanol as the eluant. Fractions shown by TLC to contain the same substance were combined to yield 1.72 g. of a viscous orange oil comprising purified trans-dl-2-acetyl-5-methyl-4,4a,5,6,7,8,8a,9-octa-10 hydro-2H-pyrrolo[3,4-g]quinoline. The orange oil was dissolved in ether and a solution of 870 mg. of maleic acid in ether added thereto. The maleate salt thus formed melted at 201-203°C. after re-crystallization from methanol ether solvent mixture 15 (1:2).
Analysis: Calculated: C, 62.05; H, 6.94; N, 8.04;
Found: C, 61.81; H, 6.82; N, 7.97.
Following the above procedure, trans-dl-2-acetyl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-
2H-pyrrolo[3,4-g]quinoline was prepared from trans-dl- 2-n-propyl-6-oxo-7-dimethylaminomethylenedeca-hydroquinoline by reaction with the potassium salt of glycine followed by acetic anhydride. The compound was purified by chromatography.
Following the above procedure, trans-dl-
1-benzy 1- 6-oxo- 7-dimethylaminomethylenedecahydro-quinoline was reacted with the potassium salt of glycine and acetic anhydride to yield trans-dl-
2-acetyl-5-benzyl-4,4a,5,6,7,8,8a,9-octahydro-2H-
pyrrolo[3,4-g]quinoline. This latter derivative was
190834
-X-5Q4SA -30-
purified by chromatography over florisil and then converted to the maleate salt. Trans-dl-2-acetyl-5-benzyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo [3,4-g]quinoline maleate melted at 162-164°C. after 5 recrystallization from a methanol-ether solvent mixture.
Analysis: calc.: C, 67.91; H, 6.65; N, 6.60;
Found : C, 67.76; H, 6.40; N, 6.58.
Example B
Preparation of trans-dl-2-Acetyl-5-n-Propyl-4,4a,-5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
A solution was prepared from 2.5 g. of trans-dl-2-acetyl-5-benzyl-4,4a,5,6,7,8,8a,9-octa-15 hydro-2H-pyrrolo[3,4-g]quinoline and 200 ml. of methylene dichloride. 4 g. of cyanogenbromide were added and the resulting mixture was stirred at ambient temperature under a nitrogen atmosphere for about 16 hours. Volatile constituents were removed 20 by evaporation in vacuo. A chloroform solution of the residue containing trans-dl-l-acetyl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline formed in the above reaction was chromatographed over 200 g. of florisil using chloroform as 25 the eluant. Fractions shown to contain the desired compound were combined and the solvent removed therefrom. Recrystallization of the residue from ether yielded crystalline trans-dl-2-acety1-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-
X-50G0A
190834
[3,4-g]quinoline melting at 135-7°C. (total yield = 630 mg.)
A mixture of 0.6 g. of trans-dl-2-acetyl-5-cyano-4,4a,5,6,7,8,8a,9-octahydro-2H-5 pyrrolo[3,4-g]quinoline, 50 ml. of glacial acetic acid, 10 ml. of water and 3 g. zinc dust was heated at refluxing temperature under a nitrogen atmosphere for about 7 hours. The reaction mixture was then filtered and the filtrate poured over ice. The 10 aqueous filtrate was then made basic with 14N
aqueous ammonium hydroxide. The aqueous alkaline layer was extracted several times with a mixture of chloroform and isopropanol. The organic extracts were combined and the combined extracts washed with 15 saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo yielded a residue which was shown to be one-spot material by TLC. The residue was dissolved in 50 ml. of dime thy If ormamide to which was added 0.8 g. potassium 20 carbonate and 0.4 ml. of n-propyl iodide. This reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for about 16 hours. The reaction mixture was then diluted with water and the diluted mixture extracted with ethyl acetate. The 25 ethyl acetate extract was washed with water and saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo yielded a residue shown to contain one major spot by TLC of the product, trans-2-acety1-5-n-propyl-4,4a,5,6,7,-30 8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
190834
Example C
Preparation of trans-dl-2-Acety1-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
3.5 Grams of trans-dl-2-acetyl-5-benzy1-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline were dissolved in 19 6 ml. of ethanol to which solution was added 0.5 g. of a 5% palladium-on-carbon catalyst. The mixture was hydrogenated in an Adams machine at room temperature at an initial
6 2
hydrogen pressure of 4.13 x 10 dynes/cm. . After 2 hours, 100% of the theoretical amount of hydrogen had been absorbed. The hydrogenation mixture was removed from the machine and the catalyst separated by filtration. TLC indicated that there were two major spots, one being starting material. The filtrate was concentrated in vacuo to yield crystalline material. Concentration of the filtrate yielded a further batch of crystalline material. These two batches were combined, dissolved in water and the aqueous solution made basic with 14N aqueous ammonium hydroxide. The alkaline layer was extracted several times with a mixture of chloroform and isopropanol. The organic extracts were combined and the combined extracts were washed with saturated aqueous sodium chloride and dried. Evaporation of the solvent yielded a residue comprising trans-dl- 2- acetyl- 4 , 4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-[3,4-g]quinoline formed in the above hydrogenation. The residue was washed with hexane. It melted at
1 908 3
K- 50 60/1
89-91°C. The maleate salt was prepared by dissolving the residue in ether and adding an excess of maleic acid in ether. The maleate salt was re-crystallized from a mixture of methanol and ether 5 and melted at 150-1°C.
Example D
Preparation of trans-dl-4,4a,5,6,7,8,8a,9-Octa-hydro-2H-pyrrolo[3,4-g]quinoline.
Three-tenths grams of trans-dl-2-acetyl-
4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g] -quinoline were dissolved in 15 ml. methanol to which was added 2 ml. of 2N aqueous sodium hydroxide. The hydrolysis mixture was stirred at ambient tempera-15 ture under nitrogen for 3/4 hour. The reaction mixture was then diluted with water and the alkaline layer extracted with a mixture of chloroform and isopropanol. The organic extract was separated, washed with saturated aqueous sodium chloride and 20 then dried. Evaporation of the solvent yielded a residue showing a single spot by TLC. The residue was dissolved in ether and an excess of an ethereal solution of maleic acid added thereto. The resulting gummy precipitate was separated, dissolved 25 in methanol, and the methanol solution diluted with ether to yield crystalline material. trans-dl-4,4a,5,6,7,8,8a,9-Octahydro-2H-pyrrolo[3,4-g]quinoline maleate thus prepared melted at 190°C. with decomposition.
1908 3 4
•X-50 6OA -34-
Example E
Preparation of l-n-Propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and l-n-Propyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone
A reaction mixture was prepared containing 4.4 g. of 4-benzoyloxycyclohexanone [prepared by the procedure of E. R. H. Jones and F. Sondheimer, J. Chem. Soc., 615 (1949)], 2.5 ml. of n-propylamine and 100 ml. toluene. The mixture was heated to reflux temperature in a nitrogen atmosphere using a Dean Stark water trap for about 2 hours. The reaction mixture was then heated to refluxing temperature for an additional 2 hours in the ^ presence of a molecular sieve to remove water. The reaction mixture was then cooled and the solvent removed by evaporation in vacuo. 4 ml. of methyl acrylate and 100 ml. of dioxane were added to the residue which was then refluxed overnight under a 2Q nitrogen atmosphere. The reaction mixture was again cooled and the volatile constituents removed by evaporation in vacuo. Chromatography of an ethereal solution of the resulting residue over 200 g. of florisil using ether as an eluant yielded a mixture 2j of l-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and l-n-propyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone: yield = 2.15 g.
190834
fr 50 GOJV
Example F
Preparation of trans-dl-2-Acetyl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-[3,4-g]quinoline
A mixture of 10 ml. of n-propyl amine and 400 ml. of toluene were cooled in an ice-water bath. A solution of 16.5 g. of ethyl a-(bromomethyl)-aerylate in 50 ml. of toluene was added thereto in dropwise fashion. The resulting mixture was stirred with cooling for about 25 minutes. Next, a solution of 11 g. of 4-benzoyloxycyclohexanone in 75 ml. of toluene was added in dropwise fashion. This new mixture was heated under a nitrogen atmosphere to refluxing temperature for about 2 3 hours. The reflux condenser was equipped with a Soxhlet extractor containing a 5A sieve to remove water.
Next the reaction mixture was cooled and the cooled mixture filtered. Evaporation of the filtrate yielded a residue comprising a mixture of 1-n-propyl-3-ethoxycarbonyl-6-benzoyloxy-l,2,3,4,5,-6,7,8-octahydroquinoline and l-n-propyl-3-ethoxy-carbonyl-6-benzoyloxy-l,2,3,4,4a,5,6,7-octahydro-quinoline. The residue was dissolved in an ether-chloroform solvent mixture and the resulting solution saturated with gaseous hydrogen chloride while maintaining the temperature in the range 0-5°C. The solvent was decanted from the crystalline hydrochloride salts thus formed. The salts were dissolved in 100 ml. of methanol. 300 ml. of
■&-5060A
190834
THF were added and the resulting solution cooled in an ice-water bath. 15 g. of sodium cyanoborohydride were added in portions to the stirred and cooled reaction mixture. After the addition had been 5 completed, the reaction mixture was stirred for another 1.25 hours after which time it was diluted with aqueous sodium bicarbonate. The aqueous alkaline mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were 10 combined and the combined extracts washed with saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent yielded trans-dl- 1-n-propyl-3-ethoxycarbonyl-6-benzoyloxydeca-hydroquinoline. The compound was dissolved in a 15 mixture of 400 ml. of methanol and 100 ml. of 2N
aqueous sodium hydroxide. This mixture was stirred at ambient temperature under a nitrogen atmosphere for 64 hours after which time the volatile constituents were removed by evaporation in vacuo. The 20 resulting residue was suspended in 800 ml. of ethanol and 15 ml. of 12N aqueous hydrochloric acid. The esterification mixture was heated to refluxing temperature and about 300 ml. of solvent removed by distillation. 300 ml. of additional ethanol were 2 5 added and the reaction mixture heated to refluxing temperature for 26 hours in an apparatus equipped with a Soxhlet trap containing a 3A sieve. The reaction mixture was cooled, diluted with aqueous sodium bicarbonate and the alkaline mixture ex-30 tracted several times with chloroform. The chloro-
190834
3r 50G0A -37-
form extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform yielded 10.3 g. of a residue which was purified by 5 chromatography over 150 g. of florisil using chloroform containing increasing (2-10%) of methanol as the eluant. Trans-dl-1-n-propyl-3-ethoxycarbony 1-6-hydroxydecahydroquinoline formed in the above reaction was obtained from the eluate frac-10 tions as a purified product.
A solution was prepared from 8.8 g. of trans-dl-1-n-propyl-3-ethoxycarbony1-6-hydroxydecahydroquinoline and 400 ml. of methylene dichloride. 41 g. of sodium acetate were added. Next, 10.8 g. 15 of pyridine hydrochloride:chromium trioxide were added and the resulting mixture stirred for about 22 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo. The resulting concentrate was dissolved in chloroform and the 20 chloroform solution chromatographed over 150 g. of florisil using chloroform containing increasing amounts (1-2%) of methanol as the eluant. Fractions shown by thin-layer chromatography to contain trans-dl-1-n-propyl-3-ethoxycarbony1-6-oxodeca-25 hydroquinoline formed in the above reaction were combined and the solvent removed from the combined extracts to yield 3.4 8 g. of the 6-oxo compound as a residue. The 6-oxo compound was dissolved in 100 ml. of toluene containing an added 25 ml. of the 30 dimethylacetal of dimethylformamide. The resulting
190834
■*-5free-A -38-
mixture was heated to refluxing temperature under a nitrogen atmosphere for 4 4 hours and was then allowed to remain at room temperature for an additional 4 days. Volatile constituents were 5 removed by evaporation in vacuo and the residue, comprising trans-dl-l-n-propyl-3-ethoxycarbonyl-6-OXO-7-(dimethylaminomethylene)decahydroquinoline formed in the above reaction, was purified by chromatographing a chloroform solution of the 10 compound over florisil using chloroform containing increasing amounts (2-5%) of methanol as the eluant. Fractions shown by TLC to contain the desired 7-dimethylaminomethylene compound were combined and the solvent evaporated therefrom in vacuo. 15 The potassium salt of glycine was prepared by reacting 2 80 mg. of potassium hydroxide with 370 mg. of glycine in 50 ml. of anhydrous ethanol. 1.3 g. of trans-dl-1-n-propyl-3-ethoxycarbonyl-6-OXO-7-(dimethylaminomethylene)decahydroquinoline 20 were added and the resulting mixture heated under a nitrogen atmosphere to reflux temperature for about 3 hours. The reaction mixture was cooled and the volatile constituents removed by evaporation in vacuo. 50 ml. of acetic anhydride were added to 25 this residue and the resulting mixture heated to reflux temperature under a nitrogen atmosphere for about 4 5 minutes thus cyclizing, decarboxylating and acetylating all in one step. Again, the reaction mixture was cooled and the volatile constituents 30 removed by evaporation. In this instance, the
1 908 3
-as—DOG OA -39-
residue was next diluted with aqueous sodium bicarbonate and the resulting alkaline aqueous layer extracted with chloroform. The chloroform extract was separated and the separated extract washed with 5 saturated aqueous sodium becarbonate and then dried. Evaporation of the chloroform yielded a residue which was chromatographed over 35 g. of florisil using chloroform containing increasing amounts (0-1%) of methanol as the eluant. Fractions shown 10 by TLC to contain the desired trans-dl-2-acetyl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo[3,4-g]quinoline formed in the above reaction were combined. The solvent was removed from the combined fractions by evaporation and the 15 resulting residue was dissolved in ether. This ether solution was treated with an excess of maleic acid, also in ether. The resulting precipitate comprising the maleate salt of trans-dl-2-acetyl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-20 octahydropyrrolo[3,4-g]quinoline melted at 179-
180°C. after crystallization from a methanol-ether solvent mixture; yield = 280 mg.
Analysis Calculated: C, 61.59; H, 7.19; N, 6.25;
Found: C, 61.32; H, 6.97; N, 6.53.
690 mg. of trans-dl-2-acetyl-5-n-propyl-7-ethoxycarbony1-4,4a,5,6,7,8,8a,9-octahydropyrrolo-[3,4-g]quinoline maleate were dissolved in ethanol and this solution added to a solution containing an excess of sodium ethylate in ethanol. The reaction
1 9083
X*-50 60A
mixture was stirred for 1/2 hour.after which time it was diluted with water and the aqueous mixture extracted with chloroform. The chloroform extract was separated, washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform yielded trans-dl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo[3 ,4-g]quinoline formed in the above reaction. The free base melted at 16 3-4°C. after recrystallization from ethanol.
Analysis calculated: C, 70.31; H, 9.02; N, 9.6 5 Found: C, 70.22; H, 8.91; N, 9.94
About 1/2 gram of trans-dl-5-n-propy1-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-[3,4-g]quinoline were dissolved in 75 ml. of tetra-hydrofuran. 1 g. of lithium aluminumhydride was added thereto in small portions. After all of the lithium aluminumhydride had been added, the reaction mixture was stirred for another 2.25 hours after 2q which time the excess lithium aluminumhydride was decomposed by the addition of ethyl acetate and any organometallic salts present decomposed by the addition of 10% aqueous sodium hydroxide. The resulting mixture was diluted with water and the aqueous layer extracted several times with chloroform. The chloroform extracts were separated and combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded as a residue, trans-dl-5-n-propy1-7-hydroxymethy1-4,4a,5,6,7,8,-8a,9-octahydropyrrolo[3,4-g]quinoline, which melted
J 908 34
at 178-180°C. after recrystallization from a ethyl acetate/ether solvent mixture.
Analysis calculated: C, 72.54; H, 9.74; N, 11.28 Found: C, 72.30; H, 9.73; N, 11.05.
About 0.4 g. of trans-dl-5-n-propy1-7-hydroxymethyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo-[3,4-g]quinoline were dissolved in 25 ml. of pyridine. 0.5 ml. of methanesulfonyl chloride were added and the resulting mixture stirred for 0.75 hours at room temperature. The reaction mixture was diluted with water and sufficient 14N aqueous ammonium hydroxide added to make the reaction mixture basic. The aqeuous mixture was extracted several times with ethyl acetate. The ethyl acetate extracts were combined and the combined extracts washed first with water and then with saturated aqueous ammonium chloride and were then dried. The residue obtained by evaporation of the solvent was chromatographed 2Q over 30 g. of florisil and the chromatogram develop with chloroform containing increasing quantities (2-4%) of methanol as the eluant. Fractions shown by thin-layer chromatography to contain the desired methanesulfonyl ester were combined and the solvent 22 removed therefrom in vacuo. The resulting residue, trans-dl-5-n-propy1-7-mesyloxymethyl-4,4a,5,6,7,-8,8a,9-octahydropyrrolo[3,4-g]quinoline was crystallized from ethanol; m.p. = 150°C. with decomposition.
t 90834
•X-5&6-0A -42-
FINAL PRODUCTS Example 1
Preparation of trans-dl-5-Methy1-4,4a,5,6,7,8,8a,9-^ octahydro-2H-pyrrolo[3,4-g]quinoline from the Corresponding 2-Acetyl Compound.
One and two-tenths grams of trans-dl-2-acetyl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline maleate were suspended in 10 100 ml. of methanol and 10 ml. of 2N aqueous sodium hydroxide were added. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for about 35 minutes and was then diluted with dilute aqueous sodium hydroxide. The resulting 15 alkaline solution was extracted several times with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and dried. Evaporation of the chloroform yielded 400 ml. of crystalline 20 material melting at 190-6°C. with decomposition. A chloroform solution of the material was then chromatographed over 30 g. of florisil using chloroform containing increasing amounts (2-5%) of methanol as the eluant. The second major component 25 to be eluted from the column consisted of trans-
dl- 5-me thy 1-4 , 4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-[3,4-g]quinoline. Fractions containing this compound were combined and the solvent removed from the combined fractions by evaporation. Recrystal-30 lization of the residue from ether yielded trans-
190834
&ee-A
dl-5-methyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-[3,4-gJquinoline melting at 200-222°C. with decomposition (80 mg.).
Analysis: calc. : C, 75. 74 H, 9.53; N, 14.72;
Found : C, 75,88 H, 9.28; N, 14.55.
Following the above procedure, trans-dl- 2-acetyl-5-n-propy1-4,4a,5,6,7,8,8a,9-octa-hydro-2H-pyrrolo[3,4-g]quinoline (4.8 g) was hydrolyzed with dilute aqueous sodium hydroxide. trans-dl-5-n-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline thus prepared was purified by chromotography over florisil using chloroform containing increasing amounts (2-10%) methanol as the eluant. Fractions shown to contain the desired product by TLC were combined and the solvent evaporated therefrom. Recrystallization of the residue from a methanol-ether solvent mixture yielded 245 mg. crystalline trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quino-line melting at 169-171°C. with decomposition; nmr peaks at 52, 384 and 510 cps. (in CDCl^).
Analysis: calc.: C, 64.65; H, 7.84; N, 8.38;
Found : C, 64.40; H, 7.62; N, 8.12.
Example 2
Preparation of trans-dl-5-n-Propy1-4,4a,5,6,7,8,-8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
The product trans-dl-2-acetyl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline (from Example B) was dissolved in 20 ml. of methanol
190834
-X—-5-0-6-QA -44-
to which was added 3 ml. of 2N aqueous sodium hydroxide. This reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 65 min. The reaction mixture was diluted with water 5 and the diluted mixture extracted several times with chloroform. The chloroform extracts were combined and the combined extracts washed with saturated aqueous sodium chloride and then dried. Evaporation of the chloroform yielded a residue which was shown 10 to contain one major spot by TLC. An ether solution of the residue, comprising trans-dl-5-n-propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline formed in the above reaction, was treated with an excess of maleic acid in ether solution, thus 15 forming the maleate salt of the base. The maleate salt was separated by filtration and recrystallized from an ether-methanol solvent mixture. trans-dl-5-n-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo-[3,4-g]quinoline maleate thus prepared melted 20 168-170°C, with decomposition; yield = 215 mg.
Example 3
The mesylate ester (prepared in Example F) can be reacted with the sodium salt of methyl-mercaptan to yield trans-dl-5-n-propy1-7-methyl-mercaptomethyl-4,4a,5,6,7,8,8a,9-octahydropyrrolots, 4-g] quinoline. •
As evidence of the utility of the compounds of formula I, it has been found that they affect _n turning behavior in rats in a test procedure
190834
X-S&&QA -45-
designed to uncover compounds useful for the treatment of Parkinsonism utilizing 6-hydroxy-dopamine-lesioned rats. In this test, nigro-neostriatal-lesioned rats are employed, as prepared 5 by the procedure of Ungerstedt and Arbuthnott, Brain Res, 24, 4 85 (19 70). A compound having dopamine agonist activity causes the rats to turn in circles contralateral to the side of the lesion. After a latency period, which varies from compound to 10 compound, the number of turns is counted over a 15-minute period.
Results obtained from testing representative compounds of formula I in the rat turning test are set forth in Table 1 below. The compounds were 15 dissolved in water and the aqueous solution injected into the rat by the intraperitoneal route at a dose level of 1 mg/kg. In the table, column 1 gives the name of the compound, column 2, percent of test animals exhibiting turning behavior, and column 3, 20 average number of turns observed in first 15 minutes after end of latency period.
< >
tsj Ul to o
H
Ul
U1
Table 1
Name of Compound trans-dl-5-n-Propyl-4,4a,5,6,-7,8,8a,9-octahydro-2H-pyrrolot3,4-g]quinoline maleate
% of Rats Exhibiting Turning Behavior
100
Average Number of Turns/rat
169
trans-dl-5-Methyl-4,4a,5,6,7,8,-8a,9-octahydro-2H-pyrrolo[3,4-g] quinoline maleate
33
.1 90834
X-5-04&A -47-
The compounds of formula I are also useful as prolactin inhibitors and as such they can be employed in the treatment of inappropriate lactation such as postpartum lactation and galac-5 torrhea. As evidence of their utility in the treatment of diseases such as those in which it is desirable to reduce the prolactin level, the compounds of formula I have been shown to inhibit prolactin according to the following procedure. 10 Adult male rats of the Sprague-Dawley strain weighing about 200 g. were housed in an air-conditioned room with controlled lighting (lights on 6 a.m. - 8 p.m.) and fed lab chow and water ad libitum. Each rat received an intra-15 peritoneal injection of 2.0 mg. of reserpine in aqueous suspension 18 hours before administration of the test drug. The purpose of the reserpine was to keep prolactin levels uniformly elevated. The compounds under test were dissolved in 10 percent 20 ethanol, and were injected intraperitoneally at doses of 0.5 and 5 mg/kg. Each compound was administered at each dose level to a group of 10 rats, and a control group of 10 intact males received an equivalent amount of 10 percent ethanol. One hour 25 after treatment, all rats were killed by decapitation, and 150 yl aliquots of serum were assayed for prolactin.
The difference between the prolactin level of the treated rats and prolactin level of the 30 control rats, divided by the prolactin level of the
1 908 3
control rats gives the percent inhibition of prolactin secretion attributable to the compounds of formula I. These inhibition percentages are given in Table 2 below. In the table, column 1 gives the 5 name of the compound; and columns 2 and 3, the percent prolactin inhibition at the 0.5 and 5 mg/kg dose levels.
o t
LO M N) (—» j—i ^
O Ln O Ul o
Table 2
Name of Compound Percent Prolactin Inhibition at Given Dose
0.5 mg/kg 5 mg/kg trans-dl-5-n-Propyl-4,4a,5,
6,7,8,8a,9-octahydro-2H-pyrrolo
[3,4-g]quinoline maleate — 95
< I
( >
trans-dl-5-Methy1-4,4af 5,6, 7,8,8a,9-octahydro-2H-pyrrolo {3,4-g]quinoline maleate
23
90
i> '
190831
In using the compounds of formula I
to inhibit prolactin secretion or to treat Parkinson's syndrome or for other pharmacologic action, a com-
2 •
pound according to formula I above in which R is C2~C3 alkyl or allyl and R"*" is H or C^-C-j alkyl, or a salt thereof with a pharmaceutically-acceptable acid, is administered to a subject suffering from Parkinsonism or in need of having his prolactin level reduced in an effective amount to treat Parkinsonism or to reduce prolactin. Oral administration is preferred. If parenteral administration is used, the injection is preferably by the subcutaneous route using an appropriate pharmaceutical formulation.
Other modes of parenteral administration such as intraperitoneal, intramuscular, or intravenous routes are equally effective. In particular, with intravenous or intramuscular administration, a water soluble pharmaceutically-acceptable salt is employed. For oral administration, the compound either as the free base or in the form of an acid addition salt thereof can also be mixed with standard pharmaceutical excipients and loaded into empty telescoping gelatin capsules or pressed into tablets. For oral administration, the compound either as the free base or i*1 form of an acid addition salt thereof, can also be mixed with standard pharmaceutical excipients and loaded into empty telescoping gelatin capsules or pressed into tablets. The oral dosage range is from about 0.01 to 10 mg. to 10 mg./kg. of mammalian weight and the parenteral dose range from about 0.00 25 to 2.5 mg./kg. Intra-
fl 9083
peritoneal dosages of 10-30 mg./kg. of trans-dl- 5-n-propy1-4,4a,5,6,7,8,8a,9-octahydro-pyrrolo-[3,4-g]-quinoline dihydrochloride resulted in no deaths, but dosages of 100-300 mg./kg. were fatal, indicating an LD5q in the range 30-100 mg./kg.
190831
Claims (16)
1. A compound of the general formula a» / 1 10 R'-I 1 I I l-R2 wherein is H or C,-C., alkyl; 2 R is C1~C3 alkyl or allyl; 3 . R is H or CH2X wherein X is CN, CONH2/ SCH^r SC^CH^, or OCH^; and the 4a, 8a bond is trans and, when R is CH2X, the compound is a 4a^, If?, 8ac^ or 4eP(, 7^, 8a^ isomer or the racemate of these isomers^ and the pharmaceutically-acceptable acid addition salts thereof.
2. A compound of claim 1 in which R"^ is H, 20 R2 is C^-C^ alkyl, and R3 is H.
3. trans-dl-5-n-Propyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
4. trans-dl-5-Methy1-4,4a,5,6,7,8, 8a,9-octahydro-2H-pyrrolo[3,4-g]quinoline.
5. trans-dl (4a,3 , 7p , 8a'X and 4arx, 7-r, 8a^)-5-n-Propyl-7-methylmercaptomethyl-4,4a,5,6,7,8,8a,9-octahydro-2H-pyrrolo [3 ,(+-£)] quinoline. -53- 190834 10 formula
6. An intermediate compound of the / • 1 I IJ R -N R" I •. Ic 15 R1 is R2 is E3 is wherein , COO (C^-C^ alkyl, CCOH, or CH2X" wherein X1 is OH, CI, 0S02 (C^-C^)alkyl, 0S02tolyi, or 0S0„phenyl; 13 with the proviso that both R and R can 2 not be H when R is C,-C., alkyl; and the 4a, 8a bond is 3 trans and, when R is other than H, the compound is a 4a$, 7ft; 8a^ or 4ao\, 7°(, 8af3 isomer or the racemate of these isomers; and their acid addition salts.
7. trans-dl-4,4a,5,6,7,8,8a,9-0ctahydro-2H-pyrrolo {^3 , 4-g[]quinoline.
8. trans-dl (4a(?, 7/3,8cKand 4aa\r 7<, 8ajS)-l-Acetyl-5-n-propyl-7-ethoxycarbonyl-4,4a,5,6,7,8,8a,9-octahydropyrrolo [3 , 4-g[] quinoline. // ; l-'t JUL 1982 • - 190831 10 20 25 -54-
9. A process for preparing a compound of the general formula R3 I • /\ A> T I /V R'-I 1 wherein R^" is H or C,-C-. alkyl; 2_5 R is C^-C^ alkyl or allyl; R3 is H_or CH^X wherein X is CN, CONH^, SCH3, S02CH3, or OCH3; and the 4a, 8a bond is trans and, when R is CI^X, the compound is a 4a^, 7^>, 8ac< or 43^, 7°^ I 8ajS isomer or the racemate of these isomers; and the pharmaceutically-acceptable acid addition salts thereof; which comprises reacting a compound of the formula R3 i i i'-i-R2 A/1 R, I H W R —N • -55- wherein R1 is (C,-C ^)alkyl-CO; 2 R is H, C^-C-j alkyl, or allyl; R3 is H or CH2Y; Y is CI, Br, OSC>2phenyl, O-tosyl, or 0S02(C1-C3)alkyl; and the 4a, 8a bond is trans and, when R^ is CH2Y, the compound is a 4a/5, 7p, 8ac*. or 4ac^,;IcA, 8aj& isomer or the racemate of these isomers,;with base to provide a compound of formula Id wherein R is H;;optionally followed by reacting with an alkyl halide to obtain a compound of formula Id where R"*" is C, -C~ alky/; 2 where R is H followed by reacting with an alkyl or allyl halide or reductive alkylation with an appropriate aldehyde and metal hydride to obtain_ a compound of formula Id where R^" is H or C,-C-. alkyl and 2 R is C^-C^ alkyl or allyl; followed by reacting a compound of formula Id where R3 is CH2Y with sodium methylate, methylmercaptan sodium salt, sodium cyanide, or sodium methanesulfinate, to obtain a compound of formula I where R3 is CH2X where X is CN, SCH3, SC^CH^, or OCH3; and optionally followed by reacting a compound 3 of formula I where R is CH-CN with hydration to obtain 3 a compound of formula I where R is CH2CONH2
10. A compound of formula I as defined in claim 1 whenever prepared by the process of claim 9. 190831 -56-
11. A pharmaceutical composition which conorises a pharma-ceutically acceptable carrier and as active ingredient a compound of formula I as defined in any of claims 1 to 5 .
12. A compound of formula I as defined in claim 1 substantially as hereinbefore described with reference to any one of the examples 1 to 3.
13 . A process according to claim 9 substantially as hereinbefore described with reference to any one of the examples 1 to 3.
14. A pharmaceutical composition as defined in claim 11 substantia lly as hereinbefore described.
15. An intermediate of formula Ic as defined in claim 6 substantially as hereinbefore described with reference to any one of the examples ■ A to F.
16. A compound of formula I as defined in claim 10 substantially as hereinbefore described. eli lilly and company By His/Their authorised Agents, A. J. PARK & SON ^er ■
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US506279A | 1979-01-22 | 1979-01-22 | |
US06/031,642 US4235909A (en) | 1979-04-19 | 1979-04-19 | Octahydro-2H-pyrrolo[3,4-g]quinolines |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ190834A true NZ190834A (en) | 1984-07-06 |
Family
ID=26673871
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ190834A NZ190834A (en) | 1979-01-22 | 1979-06-26 | Trans-dl-5-(alkyl or allyl)-4,4a,5,6,7,8,8a,9-octahydro-21 + pyrrolo(3,4-g)quinolines, |
Country Status (25)
Country | Link |
---|---|
EP (1) | EP0013788B1 (en) |
JP (1) | JPS55100385A (en) |
AR (1) | AR225012A1 (en) |
AT (1) | AT365189B (en) |
AU (1) | AU528035B2 (en) |
BE (1) | BE877328A (en) |
CA (1) | CA1131227A (en) |
CH (2) | CH641801A5 (en) |
DD (1) | DD144668A5 (en) |
DE (1) | DE2965277D1 (en) |
DK (1) | DK268979A (en) |
ES (1) | ES482084A1 (en) |
FI (1) | FI65248C (en) |
FR (2) | FR2446833A1 (en) |
GB (1) | GB2040917B (en) |
IE (1) | IE48295B1 (en) |
IL (1) | IL57665A (en) |
LU (1) | LU81440A1 (en) |
NZ (1) | NZ190834A (en) |
PH (2) | PH15118A (en) |
PL (1) | PL125785B1 (en) |
PT (1) | PT69828A (en) |
RO (1) | RO77442A (en) |
SU (1) | SU1113006A3 (en) |
ZA (1) | ZA793244B (en) |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
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IL65269A0 (en) * | 1981-03-24 | 1982-05-31 | Lilly Co Eli | 6-substituted hexahydroindazolo or hexahydroisoindolo isoquinolines |
EP0127708B1 (en) * | 1983-06-03 | 1987-09-09 | Eli Lilly And Company | Trans-dl-1-alkyl-6-alkoxyoctahydroquinolines |
IL73001A0 (en) * | 1983-09-26 | 1984-12-31 | Lilly Co Eli | Improvements in and relating to 6-oxodecahydroquinolines |
US4595754A (en) * | 1985-03-04 | 1986-06-17 | Eli Lilly And Company | Process for preparing cis N-alkylperhydroquinolines |
AR067027A1 (en) * | 2007-06-19 | 2009-09-30 | Astrazeneca Ab | DERIVATIVES OF 2, 3-DIHIDRO-1H-PIRROL [3, 4B] QUINOLIN-1-ONA, A PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM AND ITS USE IN THE MANUFACTURE OF A MEDICINAL PRODUCT FOR THE TREATMENT OF DISEASES MEDITATED BY THE MODULATION OF THE ACTIVITY OF RECEIVER GABA A. |
TWI537274B (en) * | 2011-03-14 | 2016-06-11 | 橘生藥品工業股份有限公司 | Novel octahydrothienoquinoline derivatives, pharmaceutical compositions containing the same, and their uses |
-
1979
- 1979-06-26 IL IL57665A patent/IL57665A/en unknown
- 1979-06-26 DK DK268979A patent/DK268979A/en not_active Application Discontinuation
- 1979-06-26 PT PT69828A patent/PT69828A/en unknown
- 1979-06-26 NZ NZ190834A patent/NZ190834A/en unknown
- 1979-06-26 CA CA330,551A patent/CA1131227A/en not_active Expired
- 1979-06-27 RO RO7997972A patent/RO77442A/en unknown
- 1979-06-27 FR FR7916572A patent/FR2446833A1/en active Granted
- 1979-06-27 AU AU48444/79A patent/AU528035B2/en not_active Ceased
- 1979-06-27 PH PH22695A patent/PH15118A/en unknown
- 1979-06-27 LU LU81440A patent/LU81440A1/en unknown
- 1979-06-28 EP EP79301251A patent/EP0013788B1/en not_active Expired
- 1979-06-28 DE DE7979301251T patent/DE2965277D1/en not_active Expired
- 1979-06-28 AT AT0452579A patent/AT365189B/en not_active IP Right Cessation
- 1979-06-28 JP JP8340679A patent/JPS55100385A/en active Granted
- 1979-06-28 GB GB7922532A patent/GB2040917B/en not_active Expired
- 1979-06-28 CH CH606179A patent/CH641801A5/en not_active IP Right Cessation
- 1979-06-28 BE BE1/9437A patent/BE877328A/en not_active IP Right Cessation
- 1979-06-28 FI FI792047A patent/FI65248C/en not_active IP Right Cessation
- 1979-06-29 DD DD79213989A patent/DD144668A5/en unknown
- 1979-06-29 AR AR277113A patent/AR225012A1/en active
- 1979-06-29 ES ES482084A patent/ES482084A1/en not_active Expired
- 1979-06-29 ZA ZA793244A patent/ZA793244B/en unknown
- 1979-06-29 PL PL1979216721A patent/PL125785B1/en unknown
- 1979-08-08 IE IE1210/79A patent/IE48295B1/en unknown
- 1979-11-06 FR FR7927312A patent/FR2446835A1/en active Granted
-
1980
- 1980-05-29 PH PH24086A patent/PH16181A/en unknown
- 1980-07-31 SU SU802790756A patent/SU1113006A3/en active
-
1983
- 1983-08-25 CH CH464583A patent/CH643258A5/en not_active IP Right Cessation
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